Sepsis is an often fatal clinical syndrome that develops after infection or injury. Sepsis is the most frequent cause of mortality in hospitalized patients. Experimental models of gram negative sepsis based on administration of bacterial endotoxin (lipopolysaccharide, LPS) have led to an improved understanding of the pathogenic mechanisms of lethal sepsis and conditions related to sepsis by virtue of the activation of a common underlying inflammatory cytokine cascade. This cascade of host-response mediators includes TNF, IL-1, PAF and other macrophage-derived factors that have been widely studied as acute, early mediators of eventual lethality in severe endotoxemia (Zhang and Tracey, In The Cytokine Handbook, 3rd ed. Ed. Thompson (Academic Press Limited, USA). 515-547,1998).
Unfortunately, therapeutic approaches based on inhibiting these individual "early" mediators of endotoxemia have met with only limited success in large prospective clinical trials against sepsis in human patients. It is possible to infer from these disappointing results that later-appearing factors in the host response might critically determine pathogenesis and/or lethality in sepsis and related disorders. Accordingly, there is a need to discover such putative "late" mediators necessary and/or sufficient for part or all of the extensive multisystem pathogenesis, or for the lethality, of severe endotoxemia, particularly as endotoxemia is representative of clinical sepsis and related clinical disorders.
HMG1 is a 30 kDa chromosomal nucleoprotein belonging to the burgeoning high mobility group (HMG) of non-histone chromatin-associated proteins. As a group, the HMG proteins recognize unique DNA structures and have been implicated in diverse cellular functions, including determination of nucleosome structure and stability, as well as in transcription and/or replication. The HMG proteins were first characterized by Johns and Goodwin as chromatin components with a high electrophoretic mobility in polyacrylamide gels (see in The HMG Chromosomal Proteins, E. W. Johns, Academic Press, London, 1982). Higher eukaryotes exhibit three families of HMG proteins: the HMG-1/-2 family, the HMG-14/-17 family and the HMG-I/-Y family. Although the families are distinguishable by size and DNA-binding properties, they are similar in their physical properties. HMG proteins are highly conserved across species, ubiquitously distributed and highly abundant, and are extractable from chromatin in 0.35 M NaCl and are soluble in 5% perchloric or trichloroacetic acid. Generally, HMG proteins are thought to bend DNA and facilitate binding of various transcription factors to their cognate sequences, including for instance, progesterone receptor, estrogen receptor, HOX proteins, and Oct1, Oct2 and Oct6. Recently, it has become apparent that a large, highly diverse group of proteins including several transcription factors and other DNA-interacting proteins, contain one or more regions similar to HMG1, and this feature has come to be known as the HMG1 box or HMG1 domain. cDNAs coding for HMG1 have been cloned from human, rat, trout, hamster, pig and calf cells, and HMG1 is believed to be abundant in all vertebrate cell nuclei. The protein is highly conserved with interspecies sequence identities in the 80% range. In chromatin, HMG1 binds to linker DNA between nucleosomes and to a variety of non-.beta.-DNA structures such as palindromes, cruciforms and stem-loop structures, as well as cisplatin-modified DNA. DNA binding by HMG1 is generally believed to be sequence insensitive. HMG1 is most frequently prepared from washed nuclei or chromatin, but the protein has also been detected in the cytoplasm. (Reviewed in Landsman and Bustin, BioEssays 15:539-546, 1993; Baxevanis and Landsman, Nucleic Acids Research 23:514-523, 1995). To date, no link has been established between the HMG proteins and any clinical condition or disease.
HMG1 has been alternatively identified as a heparin-binding protein abundantly expressed in developing brain and dubbed "amphoterin" for its highly dipolar sequence, comprising two internal repeats of a positively charged domain of about 80 amino acids (the HMG1 box) and an acidic C-terminal domain containing a stretch of approximately 30 continuous glutamic or aspartic acid residues. Amphoterin/HMG1 has been localized to the outer surface of the plasma membranes of epithelial, and especially neuronal cells, where it has been specifically localized to the filipodia of neural cells. Inhibition studies have suggested that amphoterin/HMG1 is required for process (neurite) extension and amphoterin/HGM1 also may be involved in neuron-glia interactions (Meremnies et al., J. Biol. Chem. 266:16722-16729,1991; Merenmies et al., J Biol. Chem. 266:16722-16729, 1991; Milev et al., J Biol. Chem. 273:6998-7005, 1998; and Salmivirta et al., Exp. Cell Res. 200:444-451, 1992). Amphoterin/HMG1 can be released from murine erythroleukemia cells after stimulation with the chemical inducer hexamethylenebisacetamide (Melloni et al., Biochem. Biophys. Res. Commun. 210:82-89, 1995). Previous study suggested that the gene product of the HMG1 gene functions as a differentiation enhancing factor by stimulating .alpha.-PKC (Melloni et al., Biochem. Biophys. Res. Commun. 210:82-89, 1995; and Melloni et al., FEBS Lett. 368:466-470, 1995).
The HMG1 gene product has been shown to interact with plasminogen and tissue-type plasminogen activator (t-PA) and effectively enhance plasmin generation at the cell surface, a system that is known to play a role in extracellular proteolysis during cell invasion and tissue remodeling. Amphoterin/HMG1 has also been shown to interact with the receptor of advanced glycosylation end products (RAGE) (Mohan et al., Biochem. Biophys. Res. Commun. 182:689-696, 1992; Yamawaki et al., J. Neurosci. Res. 44:586-593, 1996; Salmivirta et al., Exp. Cell Res. 200:444-451, 1992; and Vassalli et al., J. Clin. Invest. 88:1067-1072, 1991), (Redlitz and Plow, Baillieres Clin. Haematol. 8:313-327, 1995; and Parkkinen et al., J. Biol. Chem. 266:16730-16735, 1991).
There is a longstanding need in the art to discover improved agents that can prevent the cytokine-mediated inflammatory cascade and have therapeutic activity in a large variety of cytokine-mediated inflammatory diseases. The present invention was made during the course of investigative research to identify agents that mediate toxicity, pathogenesis and/or lethality in sepsis and other disorders related by a common activation of the inflammatory cytokine cascade.
Diseases and conditions mediated by the inflammatory cytokine cascade are numerous.
Such conditions include the following grouped in disease categories:
Systemic Inflammatory Response Syndrome, which includes: PA1 Hemolytic uremic syndrome/thrombolytic tbrombocytopcnic purpura PA1 Malaria PA1 Dengue hemorrhagic fever PA1 Leishmaniasis PA1 Leprosy PA1 Toxic shock syndrome PA1 Streptococcal myositis PA1 Gas gangrene PA1 Mycobacterium tuberculosis PA1 Mycobaclerium aviun intracellulare PA1 Pneumocystis carinii pneumonia PA1 Pelvic inflammatory disease PA1 Orchitis/epidydimitis PA1 Legionella PA1 Lyme disease PA1 Influenza A PA1 Epstein-Barr Virus PA1 Viral associated hemiaphagocytic syndrome PA1 Viral encephalitis/aseptic meningitis PA1 Premature labor PA1 Miscarriage PA1 Infertility PA1 Rheumatoid arthritis/seronegative arthropathies PA1 Osteoarthritis PA1 inflammatory bowel disease PA1 Systemic lupus erythematosis PA1 Iridoeyelitis/uveitistoptic neuritis PA1 Idiopathic pulmonary fibrosis PA1 Systemic vasculitis/Wegener's gramilornatosis PA1 Sarcoidosis PA1 Orchitis/vasectomy reversal procedures PA1 Asthma PA1 Allergic rhinitis PA1 Eczema PA1 Allergic contact dermatitis PA1 Allergic conjunctivitis PA1 Hypersensitivity pneumonitis PA1 ALL PA1 AML PA1 CML PA1 CLL PA1 Hodgkin's disease, non-Hodgkin's lymphoma PA1 Kaposi's sarcoma PA1 Colorectal carcinoma PA1 Nasopharyngeal carcinoma PA1 Malignant histiocytosis PA1 Paraneoplastic syndrome/hypercalcemia of malignancy PA1 Organ transplant rejection PA1 Graft-versus-host disease PA1 Cystic fibrosis
Sepsis syndrome PA2 Meningococcemia PA2 Trauma hemorrhage PA2 Hums PA2 Ionizing radiation exposure PA2 Acute pancreatitis PA2 Adult respiratory distress syndrome (ARDS) PA2 Post-pump syndrome PA2 Ischemia-reperfusion injury PA2 HIV infection/HIV neuropathy PA2 Meningitis PA2 Hepatitis PA2 Septic arthritis PA2 Peritonitis PA2 Pneumonia Epiglottitis PA2 E. coli 0157:H7 PA2 Familial hematophagocytic lymphohistiocytosis PA2 Sickle cell anemia PA2 Psoriasis PA2 Alopecia PA2 Multiple sclerosis PA2 Migraine headache PA2 Nephrotic syndrome PA2 Hemodialysis PA2 Uremia PA2 OKT3 therapy PA2 Anti-CD3 therapy PA2 Cytokine therapy PA2 Chemotherapy PA2 Radiation therapy PA2 Chronic salicylate intoxication PA2 Wilson's disease PA2 Hemachromatosis PA2 Alpha-1 antitrypsin deficiency PA2 Diabetes PA2 Hashimoto's thyroiditis PA2 Osteoporosis PA2 Hypothalamic-pituitary-adrenal axis evaluation PA2 Primary biliary cirrhosis
Gram positive sepsis PA3 Gram negative sepsis PA3 Culture negative sepsis PA3 Fungal sepsis PA3 Neutropenic fever PA3 Urosepsis PA3 Cardiac stun syndrome PA3 Myocardial infarction PA3 Congestive heart failure
Reperfusion Injury, which includes
Cardiovascular Disease, which includes
Infectious Disease, which includes
Obstetrics/Gynecology, including:
Inflammatory Disease/Autoimmunity, which includes:
Allergic/Atopic Diseases, which includes:
Malignancy, which includes:
Transplants, including:
Cachexia
Congenital, which includes:
Dermatologic, which includes:
Neurologic, which includes:
Renal, which includes:
Toxicity, which includes:
Metabolic/ldiopathic, which includes: